title: Activation and reversal of lipotoxicity in PC12 and rat cortical cells following exposure to palmitic acid.
abstract: Lipotoxicity involves a series of pathological cellular responses after exposure to elevated levels of fatty acids. This process may be detrimental to normal cellular homeostasis and cell viability. The present study shows that nerve growth factor-differentiated PC12 cells (NGFDPC12) and rat cortical cells (RCC) exposed to high levels of palmitic acid (PA) exhibit significant lipotoxicity and death linked to an "augmented state of cellular oxidative stress" (ASCOS). The ASCOS response includes generation of reactive oxygen species (ROS), alterations in the mitochondrial transmembrane potential, and increase in the mRNA levels of key cell death/survival regulatory genes. The observed cell death was apoptotic based on nuclear morphology, caspase-3 activation, and cleavage of lamin B and PARP. Quantitative real-time PCR measurements showed that cells undergoing lipotoxicity exhibited an increase in the expression of the mRNAs encoding the cell death-associated proteins BNIP3 and FAS receptor. Cotreatment of NGFDPC12 and RCC cells undergoing lipotoxicity with docosahexaenoic acid (DHA) and bovine serum albumin (BSA) significantly reduced cell death within the first 2 hr following the initial exposure to PA. The data suggest that lipotoxicity in NGFDPC12 and cortical neurons triggers a strong cell death apoptotic response. Results with NGFDPC12 cells suggest a linkage between induction of ASCOS and the apoptotic process and exhibit a temporal window that is sensitive to DHA and BSA interventions.
authors.affiliation: Center for Health Disparities and Molecular Medicine and Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California 92350, USA.
authors.forename: Frankis G
authors.initials: FG
authors.lastname: Almaguel
authors.forename: Jo-Wen
authors.initials: JW
authors.lastname: Liu
authors.forename: Fabio J
authors.initials: FJ
authors.lastname: Pacheco
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Casiano
authors.forename: Marino
authors.initials: M
authors.lastname: De Leon
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000633:toxicity; D005227:Fatty Acids / Q000378:metabolism / Q000633:toxicity*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress; D016716:PC12 Cells; D019308:Palmitic Acid / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
chemical_list: C505650:BNIP3 protein, rat; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019014:fas Receptor; D004281:Docosahexaenoic Acids; D012710:Serum Albumin, Bovine; D019308:Palmitic Acid; D053148:Caspase 3